Memories Misplaced, Not Lost

Long-term memories thought to have been erased in people with Alzheimer’s disease may not be lost forever, suggests recent research led by Li-Huei Tsai, Picower Professor of Neuroscience. The work of Tsai and her colleagues, described in the April 29 advance online edition of Nature, involved mice genetically engineered to show symptoms similar to those of people with neurodegen­erative disorders, such as Alzheimer’s, that affect cognitive functions. When placed in a stimulating habitat or treated with an experimental drug, the mice recovered lost memories, recalling lessons they’d learned but forgotten.

About four years ago, Tsai’s lab developed mice that could be made to produce p25, a protein implicated in some neurodegenerative illnesses. The protein caused brain-cell loss in the mice, leading to what seemed like memory loss.

In their recent work, however, the researchers found that the memories were merely out of reach. Here’s how they figured it out: For 10 minutes, mice were trained to make particular ­associations–between, say, a specific ­environment and a mild foot shock. The mice were then given four weeks to store those associations in long-term memory. At that point, their p25 production was switched on; the mice lost 25 to 30 percent of their forebrain neurons and couldn’t remember the things they’d learned. But after four weeks in an environment with stimuli such as toys, perches, exercise equipment, and other mice, the mice recovered the lost associations. “We therefore conclude that even in demented patients, memories are not necessarily lost but rather become inacces­sible,” says Tsai. “This is in line with observations that even patients suffering from severe dementia eventually experience short epi­sodes of apparent clarity, a phenomenon termed ‘fluctuating memories.’”

When the researchers later examined the animals’ brains, they found that mice whose memories had been restored did not grow new forebrain neurons to replace those that were lost. Instead, the remaining neurons formed new connections with one another. “We think that rewiring of the brain mediates, at least in part, the recovery of memories,” says Tsai.

Tsai got similar results when mice with induced brain-cell loss were treated with histone deacetylase (HDAC) inhibitors, experimental drugs that increase expression of certain genes. HDAC inhibi­tors haven’t been used in Alzheimer’s patients, though one type is being tested to treat some cancers in humans.

“It has been known for a long time that a combination of mental and physical exercises improves cognitive function in rodents and in humans,” says Tsai. Her work, she believes, shows that “the need for treatment with HDAC inhibitors would be lessened if we all keep ourselves mentally and physically engaged.”